Calvaria malformations represent one of the major groups of congenital birth defects in the human population. Despite recent advancements in medical intervention, babies born with calvarial defects often suffer multiple handicaps that significantly compromise the quality of their lives. The cranial neural crest (CMC) is an important population of multipotent embryonic progenitor cells which ultimately contribute to a diverse array of differentiated craniofacial tissues, including the calvarial mesenchyme, and plays an integral role during calvarial morphogenesis. An understanding of the manner in which CMC cells contribute to calvaria development and the molecular mechanism which regulates the fate of CNC are critical for understanding normal craniofacial development as well as CMC-related congenital malformations. Multiple growth and transcription factors have been identified as critical regulators for calvarial morphogenesis. Specifically, TGF-beta in the CMC-derived mesenchyme can induce premature cranial suture obliteration in postnatal calvaria development. It is not understood; however, what is the functional significance of TGF-b signaling in regulating the fate of the CMC-derived mesenchyme during initial calvaria morphogenesis. To address this issue, we have generated mice with conditional Tgfbr2 fl/fl; Wnt1-Cre gene ablation in neural crest cells. These Tgfbr2 fl/fl; mice show missing frontal bones and other craniofacial malformations with 100% phenotype penetrance. Significantly, disruption of the TGF-b signaling does not adversely affect the CNC migration, indicating that the TGF-b-mediated gene expression is specifically required locally during calvarial morphogenesis. Taking advantage of our Tgfbr2 fl/fl and other mutant animal models we design studies to investigate the hierarchy of TGF-b signaling in regulating the fate of CNC cells during frontal bone development by testing the hypothesis that TGF-beta signaling regulates the expression of Msx1, which in turn controls the progression of cell cycle to regulate the fate of CMC-derived mesenchymal cells during frontal bone morphogenesis. Ultimately, this study will provide a better understanding on how the TGF- beta signaling cascade regulates the fate of CNC cells during normal craniofacial development and how signaling disruption can lead to craniofacial malformations.